Phase III, Randomized, Double-Blind, Multicenter Trial Comparing Orteronel (TAK-700) Plus Prednisone With Placebo Plus Prednisone in Patients With Metastatic Castration-Resistant Prostate Cancer That Has Progressed During or After Docetaxel-Based Therapy: ELM-PC 5

Abstract

Purpose Orteronel (TAK-700) is an investigational, nonsteroidal, reversible, selective 17,20-lyase inhibitor. This study examined orteronel in patients with metastatic castration-resistant prostate cancer that progressed after docetaxel therapy. Patients and Methods In our study, 1,099 men were randomly assigned in a 2:1 schedule to receive orteronel 400 mg plus prednisone 5 mg twice daily or placebo plus prednisone 5 mg twice daily, stratified by region (Europe, North America [NA], and non-Europe/NA) and Brief Pain Inventory–Short Form worst pain score. Primary end point was overall survival (OS). Key secondary end points (radiographic progression-free survival [rPFS], ≥ 50% decrease of prostate-specific antigen [PSA50], and pain response at 12 weeks) were to undergo statistical testing only if the primary end point analysis was significant. Results The study was unblinded after crossing a prespecified OS futility boundary. The median OS was 17.0 months versus 15.2 months with orteronel-prednisone versus placebo-prednisone (hazard ratio [HR], 0.886; 95% CI, 0.739 to 1.062; P = .190). Improved rPFS was observed with orteronel-prednisone (median, 8.3 v 5.7 months; HR, 0.760; 95% CI, 0.653 to 0.885; P < .001). Orteronel-prednisone showed advantages over placebo-prednisone in PSA50 rate (25% v 10%, P < .001) and time to PSA progression (median, 5.5 v 2.9 months, P < .001) but not pain response rate (12% v 9%; P = .128). Adverse events (all grades) were generally more frequent with orteronel-prednisone, including nausea (42% v 26%), vomiting (36% v 17%), fatigue (29% v 23%), and increased amylase (14% v 2%). Conclusion Our study did not meet the primary end point of OS. Longer rPFS and a higher PSA50 rate with orteronel-prednisone indicate antitumor activity.

Randomized, Double-Blind, Placebo-Controlled Phase III Study of Tasquinimod in Men With Metastatic Castration-Resistant Prostate Cancer

“…A recent analysis of the phase III COU-AA-302 (Abiraterone Acetate in Asymptomatic or Mildly Symptomatic Patients With Metastatic Castration-Resistant Prostate Cancer) trial demonstrated a significant correlation between rPFS and OS. 22 However, the lack of correlation between rPFS and OS in this study and in other phase III studies in mCRPC [24][25][26] illustrates that significant improvements in rPFS may not always translate into longer-term survival benefit.…”

Androgen receptor antagonism drives cytochrome P450 17A1 inhibitor efficacy in prostate cancer

“…In contrast to the other CYP17 inhibitors tested, orteronel had no activity on the WT or mutant AR. In recent phase III studies of CRPC, ELM-PC 4 (chemotherapy-naive) and ELM-PC 5 (progression on docetaxel), orteronel did not meet the primary overall survival endpoints (58,59). The authors speculate that this resulted from patient crossover in Europe and North America to abiraterone and enzalutamide, which had been recently approved and were widely available in these areas.…”

Circulating Tumor Cell Number as a Response Measure of Prolonged Survival for Metastatic Castration-Resistant Prostate Cancer: A Comparison With Prostate-Specific Antigen Across Five Randomized Phase III Clinical Trials

“…It follows that inhibiting the spread of cells through the circulation would represent a therapeutic objective that is clinically meaningful. 8,[10][11][12][13][14] After the demonstration of CTC conversion rates between 35% and 40% in three phase II studies of abiraterone and enzalutamide, [15][16][17] a collaboration was initiated with the US FDA Center for Diseases and Radiologic Health to study post-treatment CTCcontaining end points as potential surrogates for survival. To do so, the CTC biomarker question was embedded in a series of phase III registration trials with a primary end point of overall survival.…”